Our successful strategy of constraining the diacylglyerol backbone (DAG) into more complicated ring structures (i.e., lactones) to overcome the entropic penalty in binding to protein kinase C (PK-C) resulted in high affinity ligands that had specifically space-oriented pharmacophoric groups. This approach was improved further by using a receptor-guided strategy that was based on the crystal structure of a phorbol ester/PK- C(delta) complex. Molecular modeling docking simulations suggested that increasing the level of branching of the side chains of the lactones would increase hydrophobic binding. This was performed on our best 4,4- disubstituted heptono-1,4-lactone template, while adjustments were made on the rest of the molecule to maintain an adequate lipophilic/hydrophilic balance. With this strategy, we have generated over 50 new compounds, some of which bind tightly to PK-C with similar subnanomolar affinities that are typical of the more complex phorbol esters. With these family of compounds, and others that are on the pipeline, we are planning to investigate isozyme selectivity. It has been known for some time that PK-C plays a role in neoplasia through the expression and activation of various isozymes varying according to the type of neoplastic tissue. For example, PK-C(epsilon) is oncogenic, and appears to help cells access entry into the cell cycle and DNA synthesis. On the contrary, PKC(delta) appears to be involved in the execution of the apoptotic program. Having access to specific inhibitors and activators of PK-C isozymes will improve our understanding of its complex signaling network and may help in developing alternative therapeutic forms against cancer. Molecular modeling has played a crucial role in our drug design by helping us select specific targets for synthesis. In parallel, we have developed very efficient chemical methods to prepare these compounds in adequate amounts. The possibilities of adapting our chemistry to a combinatorial protocol is being considered in order to improve our chances of developing specific activators, or inhibitors of individual PK-C isozymes.